Determinants of Abuse-Related Effects of Monoamine Releasers in Rats
Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation...
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ndltd-vcu.edu-oai-scholarscompass.vcu.edu-etd-15212017-03-17T08:30:01Z Determinants of Abuse-Related Effects of Monoamine Releasers in Rats Bauer, Clayton T. Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation of many of these compounds (i.e. amphetamine, methamphetamine, phenmetrazine) is their propensity for abuse; however, not all monoamine releasers are abused (i.e. fenfluramine). The goal of this dissertation was to examine pharmacological determinants of abuse-related effects produced by monoamine releasers in two preclinical assays in rats: intracranial self-stimulation (ICSS) and drug discrimination. First, this work confirmed and expanded upon previous findings that selectivity for promoting release of dopamine versus serotonin is one determinant of abuse-related effects produced by monoamine releasers. This was accomplished by determining the behavioral effects of 11 different compounds that ranged in their selectivity for dopamine versus serotonin, and a correlation was found between the ability of a compound to facilitate ICSS and the selectivity of that compound for releasing dopamine versus serotonin. These data were then submitted to a rate-dependency analysis. Here, we found that all compounds produced rate-dependent effects, but that the profile of these effects varied with a compound’s selectivity for dopamine versus serotonin. Next, the mechanism by which serotonin exerts it response rate-decreasing effects was investigated - specifically, the hypothesis that the 5HT2C receptor mediates serotonin’s abuse-limiting effects of monoamine releasers was tested. The data collected suggest that the 5HT2C receptor contributes to, but is not exclusively responsible for, the abuse-limiting effects produced by serotonin release. Finally, selectivity for norepinephrine versus dopamine was examined as a potential determinant of monoamine releaser abuse liability; results from these studies suggest that release of both dopamine and norepinephrine are required for expression of abuse-related effects in assays of ICSS and drug discrimination. These data provide a systematic examination of the determinants of the abuse-related effects produced by monoamine releasers and may contribute to development of medications with reduced abuse potentials. 2013-05-03T07:00:00Z text application/pdf http://scholarscompass.vcu.edu/etd/522 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=1521&context=etd © The Author Theses and Dissertations VCU Scholars Compass Pharmacology Dopamine Amphetamine Abuse Medical Pharmacology Medical Sciences Medicine and Health Sciences |
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Pharmacology Dopamine Amphetamine Abuse Medical Pharmacology Medical Sciences Medicine and Health Sciences Bauer, Clayton T. Determinants of Abuse-Related Effects of Monoamine Releasers in Rats |
description |
Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation of many of these compounds (i.e. amphetamine, methamphetamine, phenmetrazine) is their propensity for abuse; however, not all monoamine releasers are abused (i.e. fenfluramine). The goal of this dissertation was to examine pharmacological determinants of abuse-related effects produced by monoamine releasers in two preclinical assays in rats: intracranial self-stimulation (ICSS) and drug discrimination. First, this work confirmed and expanded upon previous findings that selectivity for promoting release of dopamine versus serotonin is one determinant of abuse-related effects produced by monoamine releasers. This was accomplished by determining the behavioral effects of 11 different compounds that ranged in their selectivity for dopamine versus serotonin, and a correlation was found between the ability of a compound to facilitate ICSS and the selectivity of that compound for releasing dopamine versus serotonin. These data were then submitted to a rate-dependency analysis. Here, we found that all compounds produced rate-dependent effects, but that the profile of these effects varied with a compound’s selectivity for dopamine versus serotonin. Next, the mechanism by which serotonin exerts it response rate-decreasing effects was investigated - specifically, the hypothesis that the 5HT2C receptor mediates serotonin’s abuse-limiting effects of monoamine releasers was tested. The data collected suggest that the 5HT2C receptor contributes to, but is not exclusively responsible for, the abuse-limiting effects produced by serotonin release. Finally, selectivity for norepinephrine versus dopamine was examined as a potential determinant of monoamine releaser abuse liability; results from these studies suggest that release of both dopamine and norepinephrine are required for expression of abuse-related effects in assays of ICSS and drug discrimination. These data provide a systematic examination of the determinants of the abuse-related effects produced by monoamine releasers and may contribute to development of medications with reduced abuse potentials. |
author |
Bauer, Clayton T. |
author_facet |
Bauer, Clayton T. |
author_sort |
Bauer, Clayton T. |
title |
Determinants of Abuse-Related Effects of Monoamine Releasers in Rats |
title_short |
Determinants of Abuse-Related Effects of Monoamine Releasers in Rats |
title_full |
Determinants of Abuse-Related Effects of Monoamine Releasers in Rats |
title_fullStr |
Determinants of Abuse-Related Effects of Monoamine Releasers in Rats |
title_full_unstemmed |
Determinants of Abuse-Related Effects of Monoamine Releasers in Rats |
title_sort |
determinants of abuse-related effects of monoamine releasers in rats |
publisher |
VCU Scholars Compass |
publishDate |
2013 |
url |
http://scholarscompass.vcu.edu/etd/522 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=1521&context=etd |
work_keys_str_mv |
AT bauerclaytont determinantsofabuserelatedeffectsofmonoaminereleasersinrats |
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1718428161459355648 |